Vinorelbine or 3′,4′-didehydro-4′-deoxy-C′-norvincaleucoblastine is a vinca alkaloid derivative compound which exhibits cytostatic effects by inhibiting tubulin polymerization. Vinorelbine inhibits mitosis at the G2+M phase. Vinorelbine and its pharmaceutical salt forms, including the tartrate salt form, are known for both as anti-neoplastic agents and anti-mitotic agents, and have been used in the treatment of non-small cell lung cancer and metastatic breast cancer.
Vinorelbine has been widely administered to cancer patients as part of chemotherapy by parenteral route through intravenous infusion or injection. Although the drug can be administered by a variety of routes, the intravenous route is one of the most commonly used administration forms of vinorelbine because it has been associated with increased bioavailability. Vinorelbine tartrate is currently manufactured in Plantes et Industrie, Gaillac, France.
Oral dosage forms, including soft capsule dosage forms, containing vinorelbine have been investigated for an oral administration route of the drug. The potential use of soft capsule dosage forms to deliver liquid forms of vinorelbine for the treatment of cancers has been investigated in Rowinsky et al., “Pharmacokinetic, Bioavailability, and Feasibility Study of Oral Vinorelbine in Patients with Solid Tumors,” J. Clin. Oncol., Vol. 12 (9) (September 1994), pp. 1754-63; Zhou et al., “Relative Bioavailability of Two Oral Formulations of Navelbine in Cancer Patients,” Biopharmaceutics & Drug Disposition, Vol. 15 (1994), pp. 577-86; and Jassem et al., “A Multicenter Randomized Phase II Study of Oral vs. Intravenous Vinorelbine in Advanced Non-small-cell Lung Cancer Patients,” Annals of Oncology, Vol. 12 (2001) p. 1375-81.
Nevertheless, development of liquid fill compositions suitable for soft capsule containment has proven difficult. In capsule fill compositions which can be used in conjunction with soft capsules, the active ingredient needs to be in the solubilized state in a solvent mixture. Furthermore, the fill composition as a whole must be chemically compatible with the capsule material and avoid degradation of the material once it has been encapsulated, as well as be inert or reduce adverse chemical interaction with the active ingredient. In the end to be useful, the biological activity of the active ingredient must not be significantly compromised. Accordingly, developmental challenges can arise in balancing all of these characteristics while accounting for the chemical nature of the active ingredient.
There is a need in the pharmaceutical field for orally administrable dosage forms containing vinorelbine as the active ingredient. Moreover, there is a need for capsule fill formulations containing vinorelbine which have improved solubility and stability characteristics and which have effective post-ingestion bioavailability.